Project Abstract N-Acetyl-lysyltyrosylcysteine-amide (KYC) is a novel, bioengineered-tripeptide inhibitor of myeloperoxidase (MPO) toxic oxidant production. During 2013, we reported that KYC effectively inhibited MPO-dependent oxidative damage to the vessel wall and improved vasodilatation in sickle cell disease (SCD) mice (PMID 23956444). Our report was the first to demonstrate that MPO was a druggable therapeutic target for reducing vasculopathy in SCD. This is important because experts in the field think vasculopathy plays a causal role the mechanisms by which SCD increases life-threatening occlusive events such as acute chest syndrome (ACS), silent cerebral infarct (SCI) and stroke. Clinical studies show that SCD induces vasculopathy and that vasculopathy increases in SCD with age. Such clinical observations begin to explain why regular transfusion therapy is so effective at reducing the incidence of silent cerebral infarct (SCI) and stroke in children with SCD from 11 to < 1% but not adults. While Endari (L-glutamine, protects RBC from oxidative damage) reduces the incidence of acute chest syndrome (ACS) in people with SCD by more than 3-fold, the incidence of ACS in people with SCD is still 8.3%, well higher than that which can be achieved in SCD children with regular transfusion therapy (< 1%). What this means is additional mechanisms must be involved in how SCD increases life-threatening events in adults. As SCD increases vasculopathy and vasculopathy plays a causal role in the mechanisms by which SCD increases SCI and stroke, we reasoned that KYC, a proven inhibitor of MPO oxidant production, may also be effective agent for reducing sickle RBC retention in lungs and cerebral events in adults with SCD. Accordingly, the goal of this revised proposal is to determine KYC pharmacokinetics (Aim 1), the feasibility of using KYC to reduce sickle RBC retention in the lungs, one of the first steps towards vasocongestion (Aim 2) as well as cerebral events in the brains of SCD mice (Aim 3). If proof-of-concept is established in these SBIR Phase I studies, ReNeuroGen, LLC will design and develop a realistic and compelling Phase II plan, raise capital from angel investors and apply for Phase II SBIR funding that will be used for contracting GLP labs to perform the preclinical safety, pharmacokinetic, pharmacodynamic and toxicology studies to generate data required for filing an IND with the FDA for using KYC to treat vasculopathy to reduce the risk of life-threatening events in the lung and brains vasculopathy in people with SCD.